Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents
BackgroundRecent studies have focused on investigating the role of cellular senescence in ovarian aging. Targeting cellular senescence has been proposed as a potential strategy to improve ovarian aging. p16 and p21 are classical molecules involved in mediating cellular senescence. In our previous st...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2025.1616965/full |
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| author | Xiaohui Lu Yongli Han Jiaming Song Qin Wan Pengfei Liu Li Chen Yufeng Wang Pingping Xue Xiuliang Dai |
| author_facet | Xiaohui Lu Yongli Han Jiaming Song Qin Wan Pengfei Liu Li Chen Yufeng Wang Pingping Xue Xiuliang Dai |
| author_sort | Xiaohui Lu |
| collection | DOAJ |
| description | BackgroundRecent studies have focused on investigating the role of cellular senescence in ovarian aging. Targeting cellular senescence has been proposed as a potential strategy to improve ovarian aging. p16 and p21 are classical molecules involved in mediating cellular senescence. In our previous study, we demonstrated that ablation of p16 is dispensable for premature ovarian aging induced by alkylating agents. In the present study, we investigated whether p21 deficiency could mitigate ovarian aging caused by alkylating agents.MethodsEight-week-old wild-type (WT, n=7) and p21 knockout (KO, n=7) female mice received a single injection of busulfan (BUL, 30 mg/kg) and cyclophosphamide (CTX, 120 mg/kg) to induce premature ovarian insufficiency (POI). Untreated WT (n=4) and p21 KO (n=4) mice served as controls. Ovaries were analyzed thirteen weeks after treatment. Ovarian reserve, folliculogenesis, cell proliferation, apoptosis and senescence, multinucleated giant cells (MGCs) and their characteristics, pro-inflammatory factors, fibrosis, ovarian stromal cell properties, and the expression of cell cycle inhibitors, including p16, p19, p27, and p53, were evaluated.ResultsFemale mice treated with alkylating agents exhibited typical features of POI, including a dramatic reduction in the number of primordial and growing follicles; defective folliculogenesis characterized by growth arrest in early-stage follicles, extensive atresia in mid-stage follicles, dysregulated FSH receptor (FSHr) expression in antral follicles, and abnormal over-activation of primordial follicles; the presence of hemosiderin-laden MGCs and fibrosis in the ovarian cortical region. p21 deficiency did not significantly mitigate these phenotypes. There were no significantly differences in the expression of pro-inflammatory factors, folliculogenesis-regulating factors, or steroidogenesis-related factors and cell cycle inhibitors between WT and p21 KO mice treated with alkylating agents. In addition, p21 deficiency did not prevent alkylating agent-induced cellular senescence.ConclusionThese results demonstrated that p21 is dispensable for POI caused by alkylating agents, suggesting that targeting p21 alone may not mitigate ovarian aging caused by alkylating agents. |
| format | Article |
| id | doaj-art-103fbd1d9f1d44c4bb400d27d66af036 |
| institution | DOAJ |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-103fbd1d9f1d44c4bb400d27d66af0362025-08-20T03:13:32ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-07-011610.3389/fendo.2025.16169651616965Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agentsXiaohui Lu0Yongli Han1Jiaming Song2Qin Wan3Pengfei Liu4Li Chen5Yufeng Wang6Pingping Xue7Xiuliang Dai8The Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, ChinaDepartment of Nursing, Changzhou Hygiene Vocational Technology College, Changzhou, Jiangsu, ChinaThe Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, ChinaThe Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, ChinaThe Department of Animal Center, Kebiao Medical Testing Center, Changzhou, Jiangsu, ChinaThe Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, ChinaThe Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, ChinaThe Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, ChinaThe Center for Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, ChinaBackgroundRecent studies have focused on investigating the role of cellular senescence in ovarian aging. Targeting cellular senescence has been proposed as a potential strategy to improve ovarian aging. p16 and p21 are classical molecules involved in mediating cellular senescence. In our previous study, we demonstrated that ablation of p16 is dispensable for premature ovarian aging induced by alkylating agents. In the present study, we investigated whether p21 deficiency could mitigate ovarian aging caused by alkylating agents.MethodsEight-week-old wild-type (WT, n=7) and p21 knockout (KO, n=7) female mice received a single injection of busulfan (BUL, 30 mg/kg) and cyclophosphamide (CTX, 120 mg/kg) to induce premature ovarian insufficiency (POI). Untreated WT (n=4) and p21 KO (n=4) mice served as controls. Ovaries were analyzed thirteen weeks after treatment. Ovarian reserve, folliculogenesis, cell proliferation, apoptosis and senescence, multinucleated giant cells (MGCs) and their characteristics, pro-inflammatory factors, fibrosis, ovarian stromal cell properties, and the expression of cell cycle inhibitors, including p16, p19, p27, and p53, were evaluated.ResultsFemale mice treated with alkylating agents exhibited typical features of POI, including a dramatic reduction in the number of primordial and growing follicles; defective folliculogenesis characterized by growth arrest in early-stage follicles, extensive atresia in mid-stage follicles, dysregulated FSH receptor (FSHr) expression in antral follicles, and abnormal over-activation of primordial follicles; the presence of hemosiderin-laden MGCs and fibrosis in the ovarian cortical region. p21 deficiency did not significantly mitigate these phenotypes. There were no significantly differences in the expression of pro-inflammatory factors, folliculogenesis-regulating factors, or steroidogenesis-related factors and cell cycle inhibitors between WT and p21 KO mice treated with alkylating agents. In addition, p21 deficiency did not prevent alkylating agent-induced cellular senescence.ConclusionThese results demonstrated that p21 is dispensable for POI caused by alkylating agents, suggesting that targeting p21 alone may not mitigate ovarian aging caused by alkylating agents.https://www.frontiersin.org/articles/10.3389/fendo.2025.1616965/fullp21cellular senescencepremature ovarian insufficiencyalkylating agentsdefective folliculogenesisprimordial follicle activation |
| spellingShingle | Xiaohui Lu Yongli Han Jiaming Song Qin Wan Pengfei Liu Li Chen Yufeng Wang Pingping Xue Xiuliang Dai Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents Frontiers in Endocrinology p21 cellular senescence premature ovarian insufficiency alkylating agents defective folliculogenesis primordial follicle activation |
| title | Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents |
| title_full | Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents |
| title_fullStr | Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents |
| title_full_unstemmed | Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents |
| title_short | Loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents |
| title_sort | loss of p21 does not protect against premature ovarian insufficiency caused by alkylating agents |
| topic | p21 cellular senescence premature ovarian insufficiency alkylating agents defective folliculogenesis primordial follicle activation |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2025.1616965/full |
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